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the capsules, all the capsules obtained at the same conditions by microfluidics will release the active virtually at the same time and moment. This is one of the major advantages of using micro-

fluidics for microencapsu-lation:

Microcapsule Uniformity.

From the industrial point of view, the main drawback of microfluidics is its pro-duction rate. Making cap-sules one-by-one entails a low production yield, and this fact makes this tech-nology less cost effective. One of the main challenges

for microencapsulation by microflui-dics is the scaling up, in other words to increase microcapsule throughput with good property control of microcapsule. The first thought would be the parallel stacking of microchips in order to ob-

tain a larger production rate, however, without any type of chip-pump system integration, the footprint and capital investment of the installation would become unaffordable. In any case, the coming years seem to be a very exciting time for the development of new micro-capsules by using microfluidics and the scaling up of this technology to reach an actual industrial scale.

We hope that the current issue will get you informed as a first step in this exciting and expanding new field of en-capsulation.

The authors acknowledge the support of the European commission under the CAP-IT Marie Curie IAPP project (IAPP-251298)

At the beginning of the 90s, Andreas Manz started to use microfabrication ap-proaches for chemical applications and today is commonly known as microfluidics. Microfluidic chips are based on micro-scale channel wherein liquids flow, enabling a high control of their movement. Since the beginning, the field has been continuously growing as the mi-crofluidics applications expand ranging from pressure regu-lators to organic synthesis and immunoassays. The growth of this field is demonstrated by the creation of specific peer-reviewed publications, such as Microfluidics and Nanofluidics and Lab-on-chip, and periodically confe-rences. Microencapsulation is included among the various uses of microfluidics. In fact, microfluidics have enabled the implementation and high control of a very complex process such as microencapsu-lation in just some millimeters of surface!

In order to manufacture particulate so-lids such as microcapsules, the process through microfluidics may have some advantages: the control of the particle size and its distribution, the capsules payload as well as the wall thickness. Beyond the capsule size control, microfluidics can also be used to produce controlled cap-sule shapes different from spherical, such as cylindric shapes. In summary, micro-fluidics are a highly advanced tool for tai-loring the physical features of microcap-sules.

Apart from the capsule geometry, another important feature for microcapsules is their wall since it is closely linked to the trigger mechanism. Within microfluidics, different processes have been used to form the capsule wall. Examples of these processes are coacervation, radical and interfacial polymerization and even col-loidosomes. These processes could pro-vide capsule walls with different types of triggers such as temperature, compres-sion, pH, and so on. If the level of trigger applied to release the active is somehow related to the geometrical properties of

EDITORIAL

MICROFLUIDICS AND MICROENCAPSULATION

Bioencapsulation Research Group © - http://bioencapsulation.net - contact@bioencapsulation.net

CONTENTS

EDITORIAL................................... 1.

CALENDAR.................................. 2

ARTICLE...................................... 3

Functional droplets, microcapsules and colloidosomes made by microfluidicsn

ARTICLE...................................... 6

Miicrofluidic generation of nanofibrillar microgels

ARTICLE..................................... 8

Microfluidic Fabrication of Smart Microcapsules with Squirting Release Mechanism

INDUSTRIAL.NEWS....................11

ARTICLE.....................................12

Microfluidic technique for measuring microcapsules

CONFERENCE.............................14

XXI International Conference on Bioencapsulation

ARTICLE.....................................16

Microfluidics: a new tool to get tunable release properties of drug loaded polymer microbeadsy

PUBLICATIONS...........................18

ASSOCIATION............................ 20

READ.ALSO.ARTICLES.IN.PREVIOUS.NEWSLETTERS

Microfluidic production of structures for encapsulation and controlled release : March 2012, 14-17

Microfluidic production of biopolymer-based Janus microbedas : June 2012, 29-31

CALL.FOR.CONTRIBUTIONS

We are waiting your contributions for the December 2013 on Enzyme encapsulation

To submit articles, news, request ...

bi@bioencapsulation.netRaul.Rodrigo.Gomez.(rodrigogomez.r@pg.com.).and..Johan.Smets.(smets.j@pg.com)..

Andreas Manz

Microfluidic Chip

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OPEN.POSITION

Professor in Food Science and technologyDevelop a research program in the field of Food Science and Technology in sec-tors relating to the eco-efficiency of milk and food processing.

Candidates should submit a letter of intent, their curriculum vitae and three letters of reference before August 18th 2013 to : Prof. Gisèle LaPointeDpt sciences des aliments et de nutritionFaculté des sciences de l’agriculture et de l’alimentation, Université LavalLocal 1312-A, Pavillon Paul-Comtois2425, rue de l’AgricultureQuébec (Québec), G1V 0A6 Canadagisele.lapointe@fsaa.ulaval.ca

.CONFERENCES.,.WORKSHOPS.....CALENDAR

PROGRAM 2013

June

ESACT.meeting.23-26 June 2013 – Lille, Franceh t t p : / / w w w . e s a c t . o r g / i n d e x .aspx?p=NewsPage&NewsId=44

16th.Industrial.Symp..and.6th.Trade.Fair..on.Microencapsu-lation.June 25-27, 2013 - Madison, USAhttp://bioencapsulation.net/2013_Ma-dison

ESACT.meeting.23-26 June 2013 – Lille, Franceh t t p : / / w w w . e s a c t . o r g / i n d e x .aspx?p=NewsPage&NewsId=44

17th.Gums.&.Stabilisers.for.the.Food.Industry.ConferenceJune 25th -28th 2013 - Glyndwr University, Wrexham, UK http://www.gumsandstabilisers.org

JuLy

7th.Annual.PSSRC.Symp.«Advanced Characterization me-thods for Solid Pharmaceutical Dosage Forms»July 5, 2013, Lille, Francehttp://www.apgi.org/pssrc_2013/

Powders.&.Grains.2013.July 8-12, 2013 - Sydney, Australiahttp://www.pg2013.unsw.edu.au

Aug

ust

ISOPOW.XII.conference.–.August 19 – 23, 2013 - Fiskebäcks-kil, Swedenhttp://www.isopow.org/

21st.International.Conference.on.Bioencapsulation.August 28-30, 2013 - Berlin, Ger-manyhttp://bioencapsulation.net/2013_Berlin

Sept

embe

r

19th. International. Sympo-sium.on.Microencapsulation.September 09-11, 2013 Pamplona, Spainhttp://www.symposiummicroencap-sulation2013pamplona.com

3rd.Conference.on.Innovation.in.Drug.Delivery.Sept 22-25, 2013 - Pisa, Italyhttp://www.apgi.org

PROGRAM 2013

Sept

embr

e

3rd.Conference.on.Innovation.in.Drug.Delivery.Sept 22-25, 2013 - Pisa, Italyhttp://www.apgi.org

Continuous. particle. proces-sing.-.TTC.workshop.189Set. 24-26 2013 – Weimar, Ger-many http://www.ttc-binzen.de/cm/index.php?id=522

Powder. handling,. quality.control,. and. applied. powder.technologySept 26-27 2013 - Copenhagen, Denmark ht tp: //powder infonew s.com / w p -content/uploads/2012/10/Course-flyer-20131.pdf

5 t h Sy m p o s ium.on. Delivery. of.Functionality. in.complex. food.systemsSept 30-Oct 3 2013 - Haifa, Israelhttp://DOF2013.org

Oct

ober

......Nano2013.ptOct 11, 2013 - Lisbon, Portugalhttp://fcts.ulusofona.pt/index.php/eventos/simposios/details/64-Na-no%202013

Pan. Coating. -. TTC. workshop.190Oct 15-17, 2013 – Binzen, Germany http://www.ttc-binzen.de/cm/index.php?id=511&L=0

Probio.2013Oct 30-31 2013 – Montreal, P.Q., Canada http://www.symposiumprobio.org

PROGRAM 2013

Nov

embe

r

Pellets.and.Micropelletsfor.oral.multiparticulatedosage.formsNov. 26-28, 2013 – Binzen, Ger-many http://www.ttc-binzen.de/cm/index.php?id=533

Dec

embr

e

GTRV.Annual.Metting.2013Dec. 2-4, 2013 – Orleans, Franceh t t p : / / w w w . g t r v . f r / ? p a g e _id=3267&lang=en

PROGRAM 2014

Janv

ier

International. Symposium. on.PolyelectronitesEin Gedi, Israel - Janauary 20-23, 2014h t t p : / / w w w . o r t r a . c o m /e v e n t s /isp2014/

Mar

ch VI. Training. School. on. Mi-croencapsulation.March 4-8, 2014 - Nha Trang, Viet Namhttp://bioencapsulation.net/2013_Nha_Trang (to be open soon)

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ENCAPSULATION THROUGH MICROFLUIDICS

The encapsulation and controlled release of reactive agents play a vital role in medicine, cosmetics, food and materials science. Some illustrative examples include the targeted release of pharmaceutical drugs, the protec-tion of flavors and fragrances or the release of healing agents in self-hea-ling materials.

Such varied applications require si-multaneous control and tuning of nu-merous capsule parameters, including their size, permeability and mechani-cal properties, which can be difficult to achieve with traditional encapsulation techniques. Instead, double emulsion templates made using microfluidics can offer substantial advantages due to its inherent precision and control of a wide range of processing variables.

In our work, we utilize established glass capillary microfluidic devices (Utada, 2005) to create deliberately tailored double emulsions that can be used directly as functional nanoliter carriers or can be further processed to obtain functional microcapsules or colloidosomes. Here, we describe a few examples of encapsulation sys-tems that can be produced through

microfluidic emulsifica-tion. We focus on water/oil/water (w/o/w) double emulsions that are ob-tained by first dripping an aqueous liquid into an immiscible oil to gene-rate droplets, which are then dripped into an ou-ter aqueous phase (Fig. 1a). By proper selection of the liquid phases we can create a variety of encapsulation systems, from responsive double emulsions to functional capsules with inorganic or polymeric shells.

The size of the double emulsions and thus the capsules can be easily varied through the flow rates and the capillary dimensions. To unders-tand the dependencies of the outer droplet size do on these parameters, we developed an ana-lytical model based on a balance between the shear forces promoting droplet break-up and

the interfacial tension opposing it (Erb, 2011). The model shows close agree-ment with experimental and literature data (Fig. 1b), allowing us to predict capsule sizes based on the flow rates, fluid parameters and device dimen-sions.

MAGNETICALLY RES-PONSIVE NANOLITER DROPLETS

By incorporating superparamagne-tic iron oxide nanoparticles (SPIONs) in either the middle oil or innermost aqueous phase of double emulsion droplets, we can create soft microcar-riers that are responsive to magnetic fields (Sander, 2012). In this case, the stability of the double emulsion is ad-justed so that at low magnetic fields the droplets can be manipulated or chained, whereas at high magnetic fields the middle oil phase is disrupted to eventually release the innermost water phase. Since the SPIONs can be selectively added either to the inner-most aqueous or the middle oil phase, undesired interactions between SPIONS and the cargo are minimized. The stability of the emulsion droplet is not only governed by the attractive magnetic force acting between them but also by the repulsive force ari-sing from surfactant molecules on the liquid surface. For magnetized single emulsion droplets stabilized by a charged surfactant, we find that the magnetic force needed to fuse them can be reduced significantly upon ad-dition of ions that screen the repulsive

.ARTICLE.

FUNCTIONAL DROPLETS, MICROCAPSULES AND COLLOIDOSOMES MADE BY MICROFLUIDICSJonathan.Sander,.Philipp.W..Chen,.André.R..Studart

Complex.Materials,.Department.of.Materials,.ETH.Zürich,.8093.Zürich,.Switzerland

Fig. 1: a) Formation of w/o/w double emulsions within a microcapillary de-vice. b) Control of emulsion sizes through tuning of flow rates. Reprinted with permission from (Chen, 2012). Copyright 2011 American Chemical Society.

Fig. 2: a) Overlay of images showing magnetically guided transport and rupture of a double emulsion droplet with magnetic particles in the innermost phase. b-d) Magne-tically induced fusion and mixing of the middle phase of two double emulsion droplets. Reprinted with permis-sion from (Sander, 2012). Copyright 2012 Wiley & Sons.

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force. The deliberate control over the stability of double emulsion droplets and our ability to transport them using magnetic fields enables us to selec-tively release reactive particles from the innermost aqueous phase in order to initiate local reactions or to mix na-noliter amounts of reagent by fusion of the middle oil phase (Fig. 2).

FUNCTIONAL COLLOI-DOSOMES

Double emulsions made by micro-fluidics can generate solid microcap-sules upon consolidation of the middle oil phase after emulsification. In one possible approach, colloidal particles can be added to the middle phase to generate hollow capsules with a shell made of nanoparticles upon removal of the oil. Such microcapsules, known as colloidosomes, exhibit a rigid shell that is selectively permeable to molecules that are small enough to diffuse through the particle intersti-tials. This controllable permeability makes colloidosomes very interes-ting for encapsulation and release applications as well as for microreac-tors. Assembly of colloidosomes from double emulsion templates allows for the formation of thick multiwalled colloidosomes (Lee, 2008). In a typical assembly process, the nanoparticles that will later constitute the shell are surface hydrophobized to enable effi-cient dispersion in the middle oil phase during the microfluidic double emulsi-fication. Because of the shorter times-cales of microfluidic emulsification as compared to conventional mixing processes, stabilization of the double emulsion templates is crucial for the successful preparation of colloido-somes. This is especially important for particle-stabilized systems due to the slow kinetics for particle adsorption at the oil-water interface. Partially

hydrolyzed poly(vinyl alcohol) added to the aqueous phase was shown to effi-ciently stabilize the double emulsion templates by rapidly forming a strong viscoelastic interfacial film together with the nanoparticles initially present in the oil phase (Sander, 2012). Since the toluene used as middle oil phase displays a certain solubility in water, it can be slowly dissolved in the conti-nuous phase while the nanoparticles are jammed together to form the cap-sule shell. By adjusting the surface chemistry of initially hydrophilic par-ticles we are able to make colloido-somes from many different materials, leading to functional shells that are for instance photocatalytically active, bioresorbable or magnetic (Fig. 3) (Sander, 2011).

POLYMER MICRO-CAPSULES WITH TUNABLE MECHANICS

Solid capsules can also be formed by using a monomer solution as the middle oil fluid and polymerizing the double emulsions via UV light. UV po-lymerization of the middle phase can

be carried out in situ and takes only a few minutes or less. To facilitate dro-plet formation through dripping at the capillary tip (Fig. 1), we use hydropho-bic, low-viscosity acrylate monomers as the middle oil phase. By choosing different monomer compositions and various additives such as plastici-zers, cross-linkers and reinforcing particles, we can easily tune the per-meability and mechanical properties of the resulting capsule shell (Chen, 2012). For example, high glass transi-tion temperature (Tg) monomers such as isobornyl acrylate (IBOA) will lead to brittle shells, while monomers with low Tg such as 2-phenoxyethyl acrylate (PEA) result in elastomeric capsules (Fig. 4). Thereby, capsule mechanics can be adapted to specific situations. For instance, brittle capsules that are stiffer but fracture at low strains are suitable for self-healing applications, where release at low external strains is desirable. In contrast, elastomeric capsules are useful in applications that demand effective protection of the encapsulant. In this case, the exten-sive and partially reversible defor-mation of the shell can absorb large amounts of strain energy, thereby pre-venting release of the encapsulant.

CONCLUSION

Double emulsions made using micro-fluidics are versatile templates for a multitude of encapsulation, delivery and storage systems. The high degree of control and compatibility with dif-ferent materials provided by micro-fluidics enables the production of highly monodisperse soft carriers or functional capsules with tailored size, chemistry, permeability and mechani-cal strength.

.ARTICLE.

Fig 3: a)-c) Scanning electron microscopy images of a colloidosome made from densely packed silica particles. Scale bars: 200 nm (in b) and 1 μm (in c). d) Mi-croscopy image of a magnetic Fe3O4-SiO2 Janus colloidosome. Reprinted with permission from (Sander 2011). Copyright 2011 American Chemical Society.

Fig. 4: Manual deformation of microcapsules filled with a fluorescent dye. Brittle cap-sules (top row, Ø 140 μm) fail after low amounts of strain, while ductile capsules (bot-tom row, Ø 140 μm) can be deformed extensively and reversibly without failure. Reprin-ted with permission from (Chen, 2012). Copyright 2011 American Chemical Society.

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6. Sander, J. S.; Studart, A. R., Mo-nodisperse Functional Colloido-somes with Tailored Nanoparticle Shells. Langmuir 2011, 27, (7), 3301-3307.

7. Chen, P. W.; Erb, R. M.; Studart, A. R., Designer Polymer-Based Microcapsules Made Using Micro-fluidics. Langmuir 2012, 28, (1), 144-152.

REFERENCES1. Utada, A.; Lorenceau, E.; Link, D.;

Kaplan, P.; Stone, H.; Weitz, D., Monodisperse Double Emulsions Generated from a Microcapillary Device. Science 2005, 308, (5721), 537-541.

2. Erb, R. M.; Obrist, D.; Chen, P. W.; Studer, J.; Studart, A. R., Predic-ting sizes of droplets made by mi-crofluidic flow-induced dripping. Soft Matter 2011, 7, (19), 8757-8761.

3. Sander, J. S.; Erb, R. M.; Denier, C.; Studart, A. R., Magnetic Trans-port, Mixing and Release of Cargo with Tailored Nanoliter Droplets. Advanced Materials 2012, 24, (19), 2582-2587.

4. Lee, D.; Weitz, D., Double Emul-sion-Templated Nanoparticle Col-loidosomes with Selective Per-meability. Advanced Materials 2008, 20, (18), 3498-3503.

5. Sander, J. S.; Isa, L.; Ruhs, P. A.; Fischer, P.; Studart, A. R., Stabili-zation mechanism of double emul-sions made by microfluidics. Soft Matter 2012, 8, (45), 11471-11477.

.ARTICLE.

.CONFERENCE.

André R. Studart has published 78 scientific papers in internatio-nal peer-reviewed journals, holds seven patents and is co-author of an undergraduate textbook on ceramic processing. His main re-search interests are on bioinspired complex materials with potential applications as medical implants, energy conversion systems and smart structures. In addition to his current activities on complex materials, he has also carried out research on novel methods for processing of refractory castables and near-net-shape advanced ce-ramics (PhD thesis), mechanical properties of dental materials and ceramics processed through col-loidal routes (post-doctoral work at ETH Zurich), and porous inor-ganic materials obtained using microfluidic techniques (post-doc-toral work at Harvard University).

Prof..Dr..André.R..StudartComplex MaterialsETH ZurichDepartment of MaterialsWolfgang-Pauli-Str. 10, HCI G 5398093 Zurich, Switzerland andre.studart@mat.ethz.ch

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INTRODUCTION

Cell fate is influenced by multiple external cues, including exposure to soluble growth factors, interactions with neighboring cells, and biophy-sical properties of the surrounding extracellular matrix (ECM) (A. Atala, 2008). Understanding and reproducing the properties of cellular microen-vironment is vital in tissue enginee-ring, wound healing and treatment of diseases. Over the past several years, three-dimensional (3D) culture in hydrogels made from synthetic and natural polymers has gained great interest in biomedical research, as it offered the ability to analyze of a va-riety of factors that determine cell fate in complex natural ECM. Furthermore, the encapsulation and subsequent cell culture of cells in micrometer-size hy-drogel modules or microspheres (mi-crogels) acting as 3D microenviron-ments offerred control over the shear forces imposed on cells, the ease of cell visualization, and the transport of oxygen, nutrients and growth factors to the encapsulated cells.

Physically crosslinked hydrogels for-med by biopolymers provide a biocom-patible, non-cytotoxic cellular envi-ronment, yet, natural polymers vary in composition and molecular weights, depending on the polymer source. The utilization of synthetic polymers

enables a systematic control of their composition and molecular weight, however chemically mediated gelation process poses the requirements of mild crosslinking chemistry, without compromising cell viability (M. P. Lu-tolf and J. A. Hubbell, 2005).

MICELLAR GELS AS 3D MICROENVIRONMENTS

Physical gelation of synthetic poly-mers is conceptually and practically appealing, as it combines the advan-tages of biopolymers and synthetic polymers and enables concomitant encapsulation of cells under close-to-physiological conditions. Self-as-sembly of block copolymers (Winnik et al. 2010) offers a very promising approach to producing artificial cellu-lar microenvironments. It is currently well-established that micelles of block copolymers organize in networks (micellar gels), due to the association governed by, e.g., hydrophobic forces, hydrogen bonding or electrostatic in-teractions between one of the blocks

of the copolymer. The re-versible nature of associa-tion offers the possibility of tuning the dynamic interac-tions between the cells and their microenvironment by local degradation and re-modelling of the matrix by the cells. Furthermore, the utilization of stimulus-res-ponsive hydrogels that dis-sociate ‘on demand’ helps to solve some of the technical challenges in post-culture cell analysis. For example, 3D gels may scatter light, which makes it difficult to analyze embedded cells by conventional microscopy. Post-culture digestion of gels with the release of cells is a beneficial for the subsequent characteriza-

tion of cells by e.g. fluorescence-ac-tivated cell sorting. Finally, hydrogels formed by cylindrical micelles (versus spherical micelles) have the struc-ture that may mimic the nanofibrillar morphology of natural ECM (Figure 1). While the self-assembly of pep-

tide amphiphiles in nanofibrillar gels showed great promise as an artificial scaffold for directed cell differentia-tion (Stupp et al. 2004), the formation of synthetic, block copolymer hydro-gels for their potential use as artificial ECMs has not been reported, although the recent work of Armes et al. 2012 showed the feasibility of this approach.

GENERATION OF NANOFRIBILLAR THERMOREVERSIBLE MICROGELS BY USING MICROFLUIDICS

Recently, microfluidics (MFs) offered a very promising route to the gene-ration of large libraries of cellular microenvironments with controllable, yet, tunable dimensions, compositions and physical properties that can be used to study a complex relationship between a large ranges of chemical compositions and biophysical proper-ties of microgels and cell fate. In the present contribution, we report MF preparation of nanofibrillar tempe-rature-responsive microgels derived from worm-like polymer micelles, and demonstrate a model system that can be used for the encapsulation and on-demand release of the encapsulated cells (Kumacheva et al. 2013).

We generated microgels from aqueous solutions of worm-like micelles of the temperature-sensitive poly(N-isopropylacrylamide)-block-polys-tyrene copolymers (Figure 2). Precur-sor droplets were generated by MF emulsification of the micellar solution in a PBS buffer at room temperature (below the low critical solution tempe-rature of the poly(N-isopropyl acryla-mide) and subsequent gelation of the droplets by increasing their tempera-ture above the gelling temperature of 28 °C.

The reported method offered the fol-lowing novel and potentially useful features: (i) The thermoreversible na-ture of the copolymer provided three crucial advantages. First, a low visco-sity of the micellar solution allowed its stable MF emulsification at room tem-

.ARTICLE.

MICROFLUIDIC GENERATION OF NANOFIBRILLAR MICROGELSDiego.Velasco..and.Eugenia.Kumacheva

.Department.of.Chemistry,.University.of.Toronto,.80.Saint.George.Street,.Toronto,.Ontario.M5S.3H6,.Canada

Figure 1. (a) Schematic of temperature mediated formation of the hydrogel from worm-like micelles. The blue and red colours correspond to the polystyrene core and the poly(N-isopropyla-crylamide) corona of the micelles, respectively. (b) Represen-tative images of the hydrogel structure. The scale bar is 5 μm.

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perature, which is a typical challenge for moderately concentrated polymer solutions. Second, polymer gelation occurred at a physiological tempe-rature. Third, following incubation at 37 °C, the microgels could be readily liquified by cooling the system below its gelation temperature and releasing potential species (Figure 3). To mimic the temporary encapsulation of cells within the thermoreversible hydro-gel, we encapsulated 6 μm-diameter poly(methyl methacrylate) micro-beads coated with a fluorescent dye fluorescein isothiocyanate ((FITC) in the gel formed by short micelles and studied microbead release upon coo-ling the gel (Figure 4). The microgels had a nanofibrillar morphology and the porosity on the scale of cellular processes. (ii) The utilization of MFs provided the capability to generate mi-crogels with narrow size distribution and at relatively high (10 s-1) frequency of microgel formation, as well as the ability to vary microgel composition in a high-throughput manner.

CONCLUSIONS

The reported microgels ex-hibit several advantageous features such as the nanofi-brillar structure and rapid, reversible sol-gel transi-tions under near-physiolo-gical conditions. Hydrogel dissociation demonstrates the concept of post-culture cell release for further cha-racterization. The ability to form microgels by the MF method offers two other potentially useful charac-teristics such as the narrow microgel size distribution and a short dissociation time. Our work offers a new concept for the generation of dynamic artificial three-dimensional microenviron-

ments for studies of cell fate.

REFERENCES1. A. Atala, Principles of Regenera-

tive Medicine, Second Ed., Acade-mic Press, Burlington, 2008.

2. M. P. Lutolf, J. A. Hubbell, Synthetic biomaterials as instructive extracel-lular microenvironments for mor-phogenesis in tissue engineering, Nat. Biotechnol., 2005, 23, 47-55.

3. A. Winnik, Nanofiber micelles from the self-assembly of block copoly-mers, Trends Biotechnol., 2010, 28, 84-92.

4. G. A. Silva, C. Czeis ler, Kr. L. Niece, E. Beniash, D. A. Harrington, J. A. Kessler, S. I. Stupp, Selective Diffe-rentiation of Neural Progenitor Cells by High-Epitope Density Nanofibers, Science, 2004, 303, 1352-1355.

5. A. Blanazs, R. Verber, O. O. Mykhay-lyk, A,. J. Ryan, J. Z. Heath, C. W. I. Douglas and S. P. Armes, Sterili-

zable gels from thermoresponsive block copolymer worms, J. Am. Chem. Soc., 2012, 134, 9741-9748.

6. D. Velasco, M. Chau, H. Thérien-Au-bin, A. Kuma chev, E. Tumarkin, Z. Jia, G. C. Walker, M. J. Monteiro and E. Kumacheva, Nanofibrillar ther-moreversible micellar microgels, Soft Matter, 2013, 9, 2380-2383.

.ARTICLE.

Eugenia.Kumachevaekumache@chem.utoronto.ca

Eugenia Kumacheva is the Canada Research Chair in Advanced Poly-mer Materials. She received her PhD degree in Physical Chemistry of Poly-mers at the Institute of Physical Che-mistry (Russian Academy of Science). She did her postdoctoral research in Polymer Physics at the Weizmann Institute of Science. Since 1996 Euge-nia Kumacheva has been a Professor in the Department of Chemistry at the University of Toronto. Her research interests include thin polymer films, polymer materials with structural hie-rarchy, synthesis of polymers in mi-crofluidic reactors, conceptualization and design of polymer nanostructured materials, materials for 3D optical memory storage, optical limiting and switching, security documents, and delivery of anticancer drugs.

Diego.Velascodvelasco@chem.utoronto.ca

Diego Velasco received his BSc de-gree in Chemistry at University of Cordoba, Spain. He did his Ph.D. in Polymeric Materials from the Com-plutense University of Madrid in 2011. His thesis was carried out in the Insti-tute of Polymer Science and Techno-logy (ICTP) and focused on the design of new stimuli sensitive polymers with applications in pharmacy and biome-dicine. In 2011 he joined the group of Professor Eugenia Kumacheva as a postdoctoral fellow. His research interest lies in the use of microflui-dic technology for the generation of microgels for cell encapsulation.

Figure 2. (a) Schematic of MF preparation of thermorever-sible micellar microgels. (b) Distribution of the diameters of droplets (dotted lines) and of the corresponding micel-lar microgels (solid lines). (c) Typical optical microscopy images of the microgels generated. The scale bar is 100 μm. The particles were imaged and analyzed at 37 °C.

Figure 3. Optical microscopy images of the microgels undergoing dissolution in PBS solution at 25 °C. The scale bar is 100 μm

Figure 4. Transmission (a,c) and fluo-rescence optical microscopy images (b,d) of FITC-coated microspheres in the gel (a,b) at 37 °C and in the liquid state at 25 °C (c,d). The scale bar is 10 μm.

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WHY SMART MICRO-CAPSULES WITH SQUIR-TING RELEASE MECHA-NISM ARE NEEDED?

In biomedical fields, microcapsules are widely investigated as effective drug delivery carriers for the treatment of diseases such as cancers or tumors. Because most anticancer drugs have harmful side effects to the normal tis-sues, the most ideal delivery carriers should be able to transport and re-lease the anticancer drugs specifically to the targeted tumor site without drug leakage during the transport process. For stimuli-triggered site-targeting delivery systems, the delivery trig-gered by physical contact may not be practicable in human body, and deli-very triggered remotely is more pre-ferable. Furthermore, some biological tissues present diffusion obstacles for drugs and/or their surrounding media are quite viscous, in which situations higher initial momentum for the drug delivery is very important for achieving a desired wide distribution of drugs at the targeted site. Therefore, smart microcapsules with squirting release mechanism, which can protect drugs before desired delivery and trigger the delivery with a large initial momentum only at diseased tissue by certain local physical or chemical signals, would be very useful for efficient therapy of a range of diseases including cancers and other site-specific diseases.

HOW TO DESIGN SMART MICROCAPSULES WITH SQUIRTING RELEASE MECHANISM?

Currently available anticancer drugs such as paclitaxel and carmustine are usually lipophilic molecules. Besides, some nanoparticles, such as proteins, liposomes and micelles, are promi-sing candidates for targeting drug delivery systems, but they usually exhibit low physical and chemical stability. Therefore, design of smart microcapsules with squirting release

mechanism for lipophilic drugs and nanoparticles is of great importance and necessity. Similar squirting re-lease behaviours can be found in some plants in nature when they eject seeds from fruits for the widest possible dis-tribution. For example, the ripe fruit of ecballium elaterium (Figure 1A), also called squirting cucumber or explo-ding cucumber, is highly turgid. On its own ripeness or being disturbed by

sniffing animals or whatsoever, the ripe fruit squirts a stream of mucila-ginous liquid containing its seeds into air for a considerable long distance by a sudden contraction of the wall of the fruit (Figure 1B). Inspired by the squirting cucumber, we design a novel family of smart microcapsules with squirting release mechanism (Figure 1C,D). The proposed micro-capsule is composed of a crosslinked smart hydrogel shell with stimuli-res-ponsive property, and encapsulates oil phase or water-based nanoparticles by dispersing the aqueous phase that containing nanoparticles into the oil phase core (Figure 1C). Upon recogni-zing environmental stimuli, the hydro-gel shell shrinks rapidly, which results in a sudden increase of the liquid pres-

sure inside the microcapsule because the oil phase in the capsule is incom-pressible. When the internal pres-sure increases to a critical value, the hydrogel shell ruptures suddenly due to its limited mechanical strength, at the same time the encapsulated subs-tances are squirted out from the mi-crocapsule together with the oil phase stream into the environment with a large momentum (Figure 1D), just like the seed-ejecting of ripe squirting cu-cumber.

MICROFLUIDICS TECHNIQUE PROVIDES AN EFFICIENT AVENUE FOR FABRICATING SMART MICROCAPSULES WITH SQUIRTING RELEASE MECHANISM

To fabricate smart microcapsules with squirting release mechanism, monodisperse multiple emulsions with precise control of interior struc-tures are necessary as templates for synthesis. Recently, a novel type of scalable microfluidic devices that based on assembly of glass capilla-ries have been developed for genera-ting monodisperse multiple emulsions with precise control of both the size and number of the inner droplets [2,3]. Figure 2 shows the schematic illustra-tion of the fabrication of monodisperse O/W/O double emulsions in a capillary microfluidic device and the template synthesis of core-shell microcapsules with squirting release mechanism [3]. The microfluidic device is assem-bled as follows. The outer diameter of cylindrical capillaries is 1.0 mm, and the inner dimension of square capil-lary tubes is also 1.0 mm. The end of injection tube and transition tube are tapered by a micropuller and then ad-justed by a microforge. Three cylindri-cal capillaries are respectively used as the injection tube, transition tube, and collection tube by aligning them coaxially inside the square capillaries. To prepare O/W/O double emulsions, the inner, middle and outer fluids are separately pumped into the injection tube, transition tube and collection

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MICROFLUIDIC FABRICATION OF SMART MICROCAPSULES WITH SQUIRTING RELEASE MECHANISMLiang-Yin.CHU

School.of.Chemical.Engineering,.Sichuan.University,.Chengdu,.Sichuan,.610065.China

Figure 1. A) A picture of squirting cu-cumber; (B) Schematic illustration of squirting cucumbers ejecting seeds together with a stream of mucilaginous liquid; (C) A microcapsule with cross-linked smart hydrogel shell containing oil phase or nanoparticles in the inner water phase of W/O emulsion core; (D) Oil phase or nanoparticles toge-ther with the oil phase stream being squirted out from the microcapsule due to the dramatic shrinkage and sudden rupture of the hydrogel shell triggered by environmental stimuli [1].

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tube of capillary microfluidic device. Monodisperse O/W/O double emul-sions generated in collection tube are collected in collection solution. After that, double emulsions in the collection solution are converted into microcapsules by polymerization of the aqueous middle layer into hydro-gel shell. The polymerization can be initiated by certain methods, inclu-ding oxido-reduction [2] and UV irra-diation [3]. Because the structures of O/W/O double emulsions can be pre-cisely controlled in microfluidics, the shell and interior structures of smart microcapsules with squirting release mechanism can be effectively control-led via microfluidics technique.

THERMO-RESPONSIVE MICROCAPSULES WITH SQUIRTING RELEASE MECHANISM

There are many cases in which envi-ronmental temperature fluctuations occur naturally and the environmental temperature stimuli can be easily de-signed and artificially controlled, ther-mo-responsive microcapsules with squirting release mechanism are de-sired for applications in these cases. With the above-mentioned microflui-dics technique, smart microcapsules with thermo-responsive hydrogel membranes can be designed and fabricated with either O/W/O double emulsions or W/O/W/O triple emul-sions as synthesis templates [2,3]. These microcapsules can be used for thermo-induced burst squirting re-lease of lipophilic substances (Figure 2) [3], nanoparticles (Figure 3) [1], and/or both hydrophilic and lipophilic substances [2]. Usually, the thermo-responsive shells of these smart mi-crocapsules are made of crosslinked

p o ly (N- is opr o -py l acr y l amide) (PNIPAM) hydro-gels. PNIPAM is a well-known t h e r m o - r e s -ponsive polymer with dramatic phase transition property when e n v i r o n m e n -tal temperature changes across its lower critical solution tempe-rature (LCST). When the tem-perature is lower than the LCST, the PNIPAM hydrogel exhibits a swollen and hydrophilic state, while it shrinks dramatically and turns to hydropho-bic when the temperature is higher than the LCST. In our microcapsule systems, the swollen and hydrophilic PNIPAM hydrogel membrane of the microcapsule can protect the encap-sulated substances when the tempe-rature is below the LCST. To ejecting the encapsulated substances into the environment with a large momentum, what we need to do is just applying a heat stimulus to increase the local environmental temperature above the LCST to cause the dramatic shrinkage of the PNIPAM hydrogel shell.

MOLECULAR-RECOGNIZABLE MICROCAPSULES WITH SQUIRTING RELEASE MECHANISM

Ion recognition and response are of fundamental importance in biologi-cal systems in nature, and also for a manifold of chemical, physical, bio-chemical and biomedical applications. Among physiologically important cations, strategies for K+-recognition attract particular attention. At certain pathological sites in living organisms, serious cytoclasis or disabled K+-Na+ pump in cell membrane results in abnormal increase of extracellular K+ concentration, which can be taken as an ion stimulus signal for designing self-regulated drug delivery sys-tems. However, K+-recognition in bio-medical field is usually challenging due to interference arising from high Na+ concentrations. Crown ethers are known for the unusual property of forming stable host-guest com-

plexes with alkali metal ions. Although 15-crown-5 complexes best with Na+ and 18-crown-6 favors K+, a 2:1 “sand-wich” complex of 15-crown-5 with K+ is also well known. Recently, we have developed a novel K+-recognition microcapsule that is able to translate the K+-recognition into a squirting release function (Figure 4). The micro-capsule membrane is composited of 15-crown-5 units as K+ sensors and N-isopropylacrylamide (NIPAM) units as actuators. The LCST of PNIPAM-based polymer shifts negatively to a lower value when the 15-crown-5 units selectively capture K+ ions to form “sandwich” complexes [4]. Therefore, at a designed operation temperature between the two LCSTs, due to the K+-recognition, the microcapsule shrinks rapidly; at the same time the pressure in the oil core increases because the oil core is incompressible and can not pass through the hydrogel membrane

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Figure 3. Thermo-triggered squir-ting microcapsule ejecting nanopar-ticles with a high momentum by the dramatic shrinkage and sudden rup-ture of hydrogel capsule membrane, just like a nanoparticle bomb [1].

Figure 2. Schematic illustration of the fabrication of mono-disperse O/W/O double emulsions in a capillary micro-fluidic device and the template synthesis of core-shell microcapsules with squirting release mechanism [3].

Figure 4. Schematic illustration of the concept of K+-recognition microcap-sule with a squirting release mecha-nism. The K+-recognition-triggered volume shrinkage of the microcap-sule membrane, which is due to the formation of a 2:1 “sandwich” com-plex of 15-crown-5 receptors with K+ ions, results in a squirting release of the encapsulated oil core [4].

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[5]. Moreover, nanoparticle filled mi-crocapsules has been utilized in fabri-cation of a tremendous array of mate-rials, including inks, paints, personal care products and foods. We think that our smart microcapsules with squir-ting release mechanism can provide new characteristics to those functio-nal materials.

ACKNOWLEDGEMENT

This article reports research of the Membrane Science and Functional Materials Group at Sichuan Univer-sity in China, and is supported by the National Natural Science Foundation of China (21136006) and the Program for Changjiang Scholars and Inno-vative Research Team in University (IRT1163).

REFERENCES1. Liu L., Wang W., Ju X.J., Xie R.,

Chu L.Y. Smart thermo-triggered squirting capsules for nanopar-ticle delivery. Soft Matter, 2010, 6: 3759-3763.

2. Chu L.Y., Utada A.S., Shah R.K., Kim J.W., Weitz D.A. Controllable monodisperse multiple emulsions. Angew. Chem. Int. Ed., 2007, 46: 8970-8974.

3. Wang W., Liu L., Ju X.J., Zerrouki D., Xie R., Yang L., Chu L.Y. A no-vel thermo-induced self-bursting microcapsule with magnetic-tar-geting property. ChemPhysChem,

2009, 10: 2405-2409.4. Liu Z., Liu L., Ju X.J., Xie R., Zhang

B., Chu L.Y. K+-recognition cap-sules with squirting release me-chanisms. Chem. Commun., 2011, 47: 12283-12285.

5. Liu L., Song X.L., Ju X.J., Xie R., Liu Z., Chu L.Y. Conversion of alcoho-lic concentration variations into mechanical force via core-shell capsules. J. Phys. Chem. B, 2012, 116: 974-979.

Prof..Liang-Yin.CHUchuly@scu.edu.cn

Dr. Liang-Yin Chu teaches and performs scientific research at Si-chuan University in China, where he directs a talented research group with a diverse and interdisciplinary focus on the development of new materials, systems and techno-logies for membrane separation, microencapsulation, controlled release, drug delivery and micro-fluidics. He has authored and coau-thored more than 300 refereed jour-nal articles, 21 patents, 3 books and 12 book chapters. He was honored as a Distinguished Young Scholar by the National Natural Science Foundation of China in 2008, and a Distinguished Professor of “Chang Jiang Scholars Program” by the Mi-nistry of Education of China in 2009.

via diffusion. When the internal pres-sure increases to a critical value, the capsule membrane ruptures suddenly due to its limited mechanical strength; as a result the encapsulated oil core squirts out.

CONCLUSIONS

We have succeeded in developing smart microcapsules with squirting release mechanism with the virtue of microfluidics technique. Micro-fluidics are efficient for generating highly controllable multiple emul-sions, which are excellent templates for synthesizing core-shell microcap-sules with squirting release mecha-nism. With smart microcapsules with squirting release mechanism as an advanced platform, stimuli-induced burst squirting release of lipophilic substances [3], nanoparticles [1], and/or both hydrophilic and lipophilic subs-tances [2] can be effectively achieved. Various capsule shells can be desig-ned and fabricated to respond to dif-ferent stimuli, such as temperature [1-3], specific ions [4] and molecules [5]. Although our initial aim is to develop a new delivery system as a drug carrier, the proposed smart microcapsules with squirting release mechanism are not only limited in the pharmaceuti-cal field. Our smart microcapsules with squirting release mechanism can also convert the variations of alcohol concentration into mechanical force

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.EXIBITORS.AT.THE.16TH.INDUSTRIAL.SYMPOSIUM.ON.MICROENCAPSULATION,.JUNE.25-27,.MADISON,.WI,.USA

www.buchi.com Quality in your hands

BUCHI provides an outstanding choice of R&D instruments for spray drying and encap-sulation from the nano- to the millimeter scale. Immobilize your enzymes, drugs, flavors, fragrances, vitamins, oils, cells or microbes in a gentle and efficient way. No matter what particle size you require – BUCHI has you covered!

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INDUSTRIAL.NEWS..

Appleton.rebranding

Appleton Papers Inc known through its development and use of coating formu-lations, coating applications and Enca-psys® microencapsulation technology is to change its name to Appvion, Inc. The change in name comes with a new look website http://www.appvion.com/.More information can be found here: http://www.appvion.com/en-us/inves-tor s / Document s / Investor s /A pple-ton%20Papers%20%20announces%20comp any % 2 0 name% 2 0 change% 2 0to%20Appvion,%20Inc.pdf

Eden. Research. plc. announces. EU.approval.granted.for.three.actives

Eden specialize in natural terpene based crop protection products and use their own novel encapsulation process based on glucan particles or yeast cell walls for aiding the delivery of volatile actives in a number of product formu-lations. Eden report that approval has now been granted for the use of active components in their lead product 3AEY for fungicidal applications. Eden has a particular interest in targeting Botrytis particularly in fruit crops. http://www.edenresearch.com/html/news/press_releases/2013/20-05-13.aspMore information on their encapsu-lation technology can be found here http://patentscope.wipo.int/search/en/WO2005113128

Capsules.incorporating.phase.change.materials

KeepCool Ltd of Israel has shown a way how functional ingredients can be pro-tected from high temperatures. The patent “Layering and microencapsu-lation of thermal sensitive biologically active material using heat absorbing material layers having increasing mel-ting points” WO/2013/069021 describes a multi-layered capsule used to protect probiotic bacteria. A primary structure incorporating the probiotic bacteria is prepared and coated with multiple layers that are separated by a PEG layer and optionally an outer enteric coating.

MIT. treating. Type. I. diabetes. with.nanospheres.

Zhen Gu and colleagues at the MIT Department of Chemical Enginee-ring and David H. Koch Institute for Integrative Cancer Research, toge-ther with researchers at Children’s Hospital Boston, North Carolina State University and University of North Carolina at Chapel Hill, and Drexel University, Philadelphia, have treated Type 1 diabetes in a model system with a glucose res-ponsive nanocapsule network. This is a fascinating piece of research uti-lizing an enzyme mediated release mechanism. Their paper Injectable Nano-Network for Glucose-Media-ted Insulin Delivery is published in ACSNano

More.information:http://pubs.acs.org/doi/abs/10.1021/nn400630x

Enzyme.triggered.layer-by-layer.nanocapsules

Mark Appleford and Marie-Michelle Kelley of The University of Texas at San Antonio have developed a novel drug delivery vehicle which is embodied in a new patent application “Logical Enzyme Triggered (Let) Layer-By-Layer Nano-capsules For Drug Delivery System”. Capsules were composed of a core of calcium carbonate surrounded by single or multiple bilayers of polystyrene sulfo-nate and poly(aliylamine hydrochloride. Surface modification is proposed where enzyme cleavable conjugates are incor-porated that can be tailored to specific drug targets which trigger release of the API.The. full-text. of. the. patent. can. be.found.athttp://patentscope.wipo.int/search/en/WO2013043812See.alsohttp://utsa.edu/commencement/spotlight/spring2013/coe.html

New. patent. for. a. novel. nutritional.supplement. to. manage. blood. glu-cose.levels

Response Scientific of Orlando, Flo-rida, US, has been assigned a patent (8,420,125) developed by their scien-tists for a medical food or nutritional supplement for managing blood glu-cose levels and a method of manu-facture. The nutritional supplement includes alpha-lipoic acid, linolenic acid, biotin, and coenzyme Q-10 at least one of which is microencap-sulated with the components pac-kaged for oral administration or formulated with a food product or in a cold drink.The.full-text.of.the.patent.ath t t p : / / p a t f t . u s p t o . g o v / n e t a c g i /n p h - P a r s e r ? S e c t 1 = P T O 1& S e c t 2= H I T O F F & d = P A L L & p = 1 & u = % 2 Fn e t a h t m l % 2 F P T O % 2 F s r c h n u m .htm&r=1&f=G&l=50&s1=8,420,125.PN.&OS=PN/8,420,125&RS=PN/8,420,125

European.Innovation.Prize.for.French.researcher

Professor Patrick Couvreur and team from Paris-Sud Universi-ty in Paris win the inventor prize for their techonlogy of anti-can-cer molecule nanoencapsula-tion, allowing to release precisely the drug inside the cancer cells while limiting the adverse effects. More.information.(in.French)http://sciencesetavenir.nouvelobs.com/sante/20130528.OBS0942/des-nano-capsules-medicales-francaises-pri-mees.html

TO.CONTRIBUTE,.CONTACT

Craig.DuckhamCD R&DConsultancy ServicesCraig.Duckham@CDRnD.co.ukTwitter: @CDRnDhttp://www.CDRnD.co.ukhttp://uk.linkedin.com/in/scduckham

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INTRODUCTION

For liquid-filled artificial capsules, the membrane properties play an essen-tial role in the control of the capsule deformation and possible breakup (to be induced or prevented depending on the application). But measuring the mechanical properties of the mem-brane is difficult as the capsules are typically small (from a few microns to a few millimeters), fragile and often highly deformable. We have designed a new technique that allows the mea-surement of the mean shear elastic modulus on a population of initially spherical capsules by coupling micro-fluidic experiments with a mechani-cal model. The experiments consist of flowing a capsule suspension in a small pore that has transversal di-mensions comparable to those of the suspended capsules [1,2]. The hydro-dynamic stresses and the constraints due to the channel confinement cause large deformations of the capsules. They are function of the flow strength and of the particle intrinsic physical properties such as the relative size compared to the channel section and membrane constitutive behaviour. The capsule deformation, volume and velo-city can be measured simultaneously by means of image analysis. A sophis-ticated model of the flow of a capsule in a small pore then allows one to infer the membrane mechanical properties from the experimental results. The technique is hereafter illustrated on spherical capsules enclosed by a thin polymerized ovalbumin membrane.

PRINCIPLE OF THE MI-CROFLUIDIC TECHNIQUE

A dilute suspension of artificial cap-sules (mean radius a) in a viscous fluid (viscosity µ) is flowed at different flow rates in a cylindrical tube (radius h) or in a square section microfluidic tube (side 2h). The micro-channels have a cross section comparable to the cap-sule dimension, i.e. a/h = O(1). The deformation and velocity of one cap-sule are observed with a transmission microscope connected to a high reso-lution high-speed camera. Depending

on the size ratio and velocity, slug or parachute profiles are observed as shown in Figure 1. The profile extrac-tion is done with ImageJ. We then cal-culate the total length L of the profile, its axial length La and its surface S as shown in Figure 1. In a circular sec-tion, the initial radius of the capsule can be easily inferred from the defor-med profile by assuming axisymmetry. In a square section pore, we determine an apparent radius aapp of the capsule as the radius of a sphere which has the volume 2Sh. In order to analyze the ex-periments, a mechanical model of the set-up is needed.

MECHANICAL MODEL OF THE MOTION OF A CAPSULE IN A PORE

An initially spherical capsule (radius a) flows along the z-axis of a micro-fluidic channel with a square or cir-cular cross-section (dimension 2h) in the perpendicular xy-plane. The interior and exterior of the capsule are incompressible Newtonian fluids with the same density and viscosity. The thin membrane of the capsule is an impermeable hyperelastic isotropic material with surface shear modulus Gs and area dilatation modulus Ks. The bending resistance is neglected. The membrane constitutive law must be defined to account properly for the large deformation of the capsule. We have considered two laws, which have the same small deformation behaviour but which are either strain-softening (neo-Hookean law) or strain-harde-ning (Skalak type law) under large deformation. Apart from the capsule membrane mechanical properties, the two other main parameters of the problem are the size ratio a/h between the capsule initial ra-dius and the channel cross dimension, and the capillary num-ber Ca = µV/Gs, which measures the ratio between viscous and elastic forces, where V is the mean exter-nal undisturbed flow velocity along the z-

axis of the channel. The flow Reynolds number is assumed to be very small, so that the internal and external liquid motions satisfy the Stokes equations. We assume that the membrane velo-city is equal to the fluid velocity and that the elastic load on the membrane is due to the viscous traction exerted by the fluid flows.

This problem represents a complica-ted fluid-structure interaction pro-blem, where the fluid flows are gover-ned by viscous effects and where the structure deformation may be large. In absence of an available analytical solution, a numerical solution must be sought. We solve the problem equa-tions by coupling a boundary integral technique for the fluid flows to a finite element technique for the membrane mechanics. Details on the problem equations and their solution can be found in [3,4]. The advantage of the procedure is that only the boundaries of the flow domain (channel entrance and exit section, walls and capsule membrane) are discretized. The model inputs are the capillary number Ca, the size ratio a/h and the membrane law. The model outputs are the capsule centre velocity vo, the steady deformed capsule shape, the additional pressure drop due to the capsule and the elastic stress distribution in the membrane. From the deformed profile, it is pos-sible to compute the evolution of the total length L, of the parachute depth Lp = L - La and of the apparent capsule radius aapp with size ratio a/h and Ca. The model also yields the elastic ten-sion distribution in the membrane. If a failure criterion is known for the mem-brane, it is then possible to infer whe-ther there is a risk of breakup.

All the following results pertain to an

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MICROFLUIDIC TECHNIQUE FOR MEASURING MICROCAPSULESA.-V..Salsac,.E..Leclerc.and.D..Barthès-Biesel

Laboratoire.de.Biomécanique.et.Bioingénierie,.Université.de.Technologie.de.Compiègne,.France

Figure 1 Capsule profile extraction from an ex-perimental image. Images reproduced from [3]

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equilibrium state, where the capsule is centred on the tube axis. At steady state, the membrane and the internal fluid are motionless. This means that the assumption of equal viscosity for the internal and external liquids does not limit the validity of the results: the viscosity ratio only influences the time the capsule needs to reach a steady state (this time increases as the inter-nal viscosity increases). Furthermore, as the pressure inside the capsule is uniform, the curvature at the capsule upstream tip must be larger than at the rear to account for the viscous pressure drop in the lubrication film around the capsule. This explains why parachute or slug shapes are obtai-ned. For a given membrane constitu-tive law, charts of the main geometri-cal parameters (L, Lp, aapp) and of the relative capsule velocity vo/V are com-puted as functions of Ca for different size ratios. They are given for a strain-softening and for a strain-hardening law in the case of axisymmetric flow in a cylindrical pore [2]. The same charts have been recently published for the flow in a square section pore [3,4]. As an example, we show these charts in a square section tube for a strain-softe-ning membrane in Fig. 2. One can see for instance that there exists a critical value of Ca for which Lp > 0, indicating

the appearance of a parachute. The charts can be used to analyze experi-ments on flowing capsules and deduce the mechanical properties by inverse analysis.

EXAMPLE: CAPSULES ENCLOSED BY A POLY-MERISED OVALBUMIN MEMBRANE

We illustrate the inverse analysis technique on artificial capsules with a polymerised ovalbumin membrane prepared using an interfacial cross-linking method [5]. The capsules (a = 31 ± 7 µm) are suspended in glycerin with a concentration 2.2% (viscosity µ = 0.7 Pa.s at 23°C). The suspension is injected into a square micro-fluidic tube (h = 27.4 ± 0.5 µm) by means of a syringe pump at different flow rates. A typical deformed pro-file is shown in Fig. 1. If one first models the capsule membrane as strain-softening, the charts of Fig. 2

can be used to determine which value of a/h and of Ca give the best corres-pondence between the experimental and numerical values of aapp, L and Lp. As a check, one can compare the experimental and numerical profiles obtained for these values of Ca and a/h and note that the superposition is very good as shown in Fig. 3. The velocity ratio vo/V is deduced from the values of Ca and a/h, and hence the mean flow velocity V, since vo is measured expe-rimentally. It is then possible to infer the shear elastic modulus of the mem-brane Gs = µV/Ca.

We have analyzed a population of 18 capsules of different initial sizes, flowing through the square-section capillary tube at different flow rates. The mean elongation of each capsule is defined as the ratio between the profile perimeter and 2πa. For a mean elongation ranging from 1 (no defor-mation) to 1.25, we find a constant value Gs = 0.036 ± 0.006 N/m, which is in agreement with former results on ovalbumin capsules prepared under the same conditions [2]. The same analysis with a strain-hardening law yields a value of Gs that decreases with increasing deformation. It thus seems that the cross-linked ovalbumin mem-brane is strain-softening rather than strain-hardening.

CONCLUSION

The present technique enables to infer plausible mechanical properties of an artificial capsule membrane from ex-periments, in which the capsule has to deform to flow inside a small pore with cross-dimensions of the same order as those of the capsule. The method is based on the coupling of experi-mental observations with a rigorous mechanical model of the system. The method works well, if the deformation of the capsule is large enough. Thus,

Figure 3 Comparison between extracted experimental profiles (circles) and numerical profiles (full line) obtai-ned for a strain-softening law. Left: a/h = 0.9, Ca = 0.08; right: a/h = 1.1, Ca = 0.03. Images reproduced from [3].

Figure 2. Charts of the deformation parameters for a capsule with a strain-softening membrane, flowing in a square section microfluidic pore. Images reproduced from [4]

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it is best to use a pore, such that the size ratio of the capsules is of order unity. Small capsules (a/h < 0.8) have to be flowed fast to be deformed with concomitant difficulties of observation leading to profile fuzziness. In order to reach large deformation, while kee-ping the capsule velocity moderate, a high viscosity suspending liquid is necessary. But the price to pay is that the high viscous pressure drop inside the micro-channel may lead to the destruction of the connections. The advantage of using a square-section channel rather than a cylindrical one is linked to the easy fabrication of mi-crofluidic tubes of any size and to the easy connection with the propulsion device. Furthermore, this system can be built in a microfluidic fabrication device to monitor the properties of the capsules in situ [6]. We note that it is even possible to infer the large defor-mation behaviour of the membrane, at least to decide whether it is strain-sof-tening or hardening.

REFERENCES1. Y. Lefebvre, E. Leclerc, D. Bar-

thès-Biesel, J. Walter, F. Edwards-Lévy Flow of artificial microcap-sules in microfluidic channels: A

method for determining the elas-tic properties of the membrane. Phys. Fluids, 20, 123102 (2008).

2. T. X. Chu, A.-V. Salsac, E. Leclerc, D. Barthès-Biesel, H. Wurtz, F. Ed-wards- Lévy Comparison between measurements of elasticity and free amino group content of ovalbumin microcapsule membranes: discri-mination of the cross-linking de-gree. Int. J. of Colloid Interface Sci., 355, 81–88 (2011).

3. X.-Q. Hu, A.-V. Salsac, D. Barthès-Biesel Flow of a spherical capsule in a pore with circular or square cross-section. J. Fluid Mech., 705, 176–194 (2012).

4. X.-Q. Hu, B. Sévénié, A.-V. Salsac, E. Leclerc, D. Barthès-Biesel, Charac-terization of membrane properties of capsules flowing in a square-sec-tion microfluidic channel: effects of the membrane constitutive law, Phys. Rev. E, In Press (2013).

5. F. Edwards- Lévy, M. C. Andry, M. C. Lévy Determination of free amino group content of serum albumin microcapsules using trinitrobenze-nesulfonic acid: effect of variations in polycondensation pH. Int. J. Phar-maceutics, 96, 85–90 (1993).

6. T. X. Chu, A.-V. Salsac, D. Barthès-Biesel, L. Griscom, F. Edwards-Lé-vy, E. Leclerc Fabrication and in situ characterization of microcapsule in a microfluidic system. Microfluid. Nanofluid., 14, 309–317 (2013).

Anne-Virginie.SalsacLaboratoire de Biomécanique et Bioingénierie (UMR CNRS 7338), UTCCS60319, 60203 Compiègne, FranceTel: +33 (0)3 44 23 73 38a.salsac@utc.fr

After completing her Ph.D. in bio-fluids in the Department of Mecha-nical and Aerospace Engineering at the University of California San Diego (USA) and in the Laboratory of Hydro-dynamics (LadHyX) at the Ecole Poly-technique (France) in 2005, Anne-Virginie Salsac became lecturer in the Department of Mechanical Engi-neering at University College Lon-don (UK). Since 2007, she is a CNRS researcher in the Biomechanics & Bioengineering Laboratory at the Université de Technologie de Com-piègne. Her research is mainly fo-cused on the multi-physics modelling of physiological flows. She studies blood circulation from vascular flows to the microcirculation in healthy and diseased conditions, as well as intra-vascular or percutaneous therapeu-tic techniques coupling experimental and numerical approaches.

XXI INTERNATIONAL CONFERENCE ON BIOENCAPSULATION

August.28-30,.2013

Berlin,.Germany

PROGRAM

SESSION 1. Agriculture and environmental issuesChaired by A. M. Gimeno, GAT, Austria (to be confirmed)Chaired by A. Nussinovitch - Hebrew Univ. of Jerusalem, Israel

SESSION 2. Bioactives in Food and FeedChaired by G. Reineccius - Univ. Minnesotas, USAChaired by M.I. Re - Emac, France

SESSION 3. Engineering and innovative technologiesChaired by Z. Zhang - Univ. Birmingham, UKChaired by L. Fonseca - Instituto Superior Técnico, Portugal

SESSION 4. Biomedical applicationsChaired by H. Stoover - McMaster Univ., CanadaChaired by J. Irache - Univ. Pampelona, Spain

SESSION 5. Analytical methodsChaired by C. Sociacu - Prolanta, RomaniaChaired by G. Meester, DSM, Netherlands

More information : http://Bioencapsulation.net/2013_Berlin

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CONFERENCE.

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.EXIBITORS.AT.THE.16TH.INDUSTRIAL.SYMPOSIUM.ON.MICROENCAPSULATION,.JUNE.25-27,.MADISON,.WI,.USA

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INTRODUCTION

Pharmaceutically active ingredients can be administered orally, intrave-nously, intramuscularly or subcu-taneously but oral administration remains the most physiological and convenient way of delivering drugs (Delie and Blanco-Príeto, 2005). One can develop systems that carry drug to a specific region within the gastrointes-tinal tract for a local or systemic action. Different dosage forms are used for oral administration but microparticles have certain advantages over single unit systems like less chance of dose dumping and local irritation, increased bioavailability, low dependence on gas-tric emptying time etc. Microencapsu-lation is used to develop microparticles where active materials are entrapped through the formation of thin coa-ting materials for protection of drug, controlled release, reduced adminis-tration frequency, patient comfort and compliance (Khan et al., 2013). Conven-tional methods (emulsion solvent eva-poration, emulsion solvent diffusion etc.) for microencapsulation show poor drug loading, polydispersity and batch to batch variation (Holgado et al., 2008). Microfluidics can be a suitable alter-native to overcome these problems by producing microparticles having a very narrow size distribution (Serra and Chang, 2008).

MICROBEAD FABRICATION

A simple and low cost off-the-shelf co-axial microfluidic device (Fig 1) was used to synthesize copolymer micro-beads with different ethyl acrylate (EA) and tripropylene Glycol Diacrylate (TPGDA, a difunctional monomer) weight contents, encapsulating a lipo-philic model drug (ketoprofen). The monomer dispersed phase, admixed with the drug, was injected into a conti-nuous phase (carob solution of 2150 cps viscosity) through a fused silica capilla-ry (I.D. 50 µm) placed in an outlet PTFE tubing (I.D. 16 or 18 mm). Once mono-mer droplets are generated they are polymerized downstream by UV irra-diation having and intensity of 140 mW/

cm2 (Hamamatsu Lightningcure LC8) (Fig 1). Microbeads were then collec-ted at the exit of the tubing and washed with distilled water, dried and stored in glass vials until further use.

Size analysis was performed by Hiris version 3 (R&D VISION) software and has shown microbead size decreased by increasing the ratio of continuous to dispersed phase flow rates (Qc/Qd) with coefficient of variation less than 5 % (highly monodispersed microbeads) for each formulation tested (different EA weight contents). In these condi-tions we operated in dripping mode (Fig 2.A). From optical and SEM microscopy each formulation produced spherical beads with uniform surface which gets rough with increasing content of ethyl acrylate.

FTIR spectra confirmed complete poly-merization of comonomer droplets by observing the absorbance of acrylate double bond stretching and bending

vibrations at 1636 and 808 cm-1 respectively. Pure ketoprofen showed keto-nic and carbonyl peaks at 1659 cm-1 and 1692 cm-1 respectively. In FTIR spectra of microbeads one observed ketoprofen ketonic peak at 1659 cm-1 but could not see carbo-nyl peak corresponding to 1692 cm-1. This could be due to disruption of crystalline dimer as a result of the interaction between ketoprofen car-

boxylic group and carbonyl group of polymer. Afterwards carboxylic acid stretching vibration is shifted to higher wavelengths and is overlapped by strong ester vibrations of monomers at 1725 cm-1 (Fig 3). These results are further confirmed by DSC studies for which characteristic peaks of ketopro-fen were not observed. DSC thermo-gram further indicates the conversion of crystalline form to amorphous form. These results were further confirmed by XRD where diffraction peaks of keto-profen at 6, 14 and 18ϴ are reduced in XRD patterns of all the formulations.

Low encapsulation efficiency was observed in pure poly(TPGDA) micro-beads but was increased by increasing the amount of EA. It is believed that this results from the increase in the num-ber of carbonyl groups in polymer chain with increased EA weight content. Here caroboxyl group of ketoprofen will inte-ract with carbonyl group and will not

.ARTICLE.

MICROFLUIDICS: A NEW TOOL FOR TUNABLE RELEASE PROPERTIES OF DRUG LOADED POLYMER MICROBEADSa,b,c.Ikram..Ullah..Khan,.bChristophe..A..Serra,.aNicolas.Anton,.aThierry.Vandamme

a,b.University.of.Strasbourg,.France.-.c.Government.College.University,.Faisalabad,.Pakistan

Figure 1. Schematic drawing of the microfludic setup.

Fig 2: Snapshots of the droplet formation for different Qc/Qd ratio (Scale bar = 500 μm) (A). Optical images of unpolymerized droplets (B) and polymerized beads (C), SEM micrographs of micro-beads (D) Typical microbeads size histogram for Qc/Qd=120 (E) (Adapted from Khan et al., 2013).

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mer Particles. Chemical Enginee-ring & Technology 31, 1099-1115.

Christophe.A..SERRA.G2IP/ICPEES - UMR 7515 CNRSECPM - UdS25 rue Becquerel 67087 Strasbourg Cedex2 – FranceTel. 33 (0)368 852 718ca.serra@unistra.frhttp://icpees.unistra.fr/caserra

Christophe A. SERRA is Profes-sor at the University of Strasbourg teaching at the European School of Chemistry, Polymers and Mate-rials Science (ECPM). He received his MS and PhD degrees in chemi-cal engineering from the National Engineering School of the Chemi-cal Industries (Nancy) and Paul Sa-batier University (Toulouse), res-pectively. His researches concern the development of intensified and integrated microfluidic-assisted polymer processes for the synthe-sis of architecture-controlled poly-mers and functional microstructu-red polymer particles.

diffuse to surrounding media having pH around 6 to 7 during polymerization. Encapsulation efficiency was higher in small size beads than larger which may be due to the fact that smaller droplet polymerizes faster than larger thus reducing the diffusion of ketoprofen.

Drug release studies were carried out in USP phosphate buffer solution of pH 1.2 and 6.8 and indicated that all formula-tions released a small quantity of keto-profen at pH 1.2. At pH 6.8 the release rate depended on the concentration of EA and increased with an increase in EA weight content (Fig 4). Pure poly(TPGDA) microbeads forms a very dense polyme-ric network where dissolution media cannot access easily to dissolve and diffuse the drug. But when the concen-tration of EA is increased, it makes loose matrix that helps in faster imbibition of surrounding fluid and diffusion of keto-profen. Furthermore one was able to improve the drug release by decreasing the size of microbeads (Fig 4).

CONCLUSION

Capillary-based co-flow microfluidic setup was found conveniently appro-priate to encapsulate ketoprofen in monodispersed polymeric microbeads while starting from monomers. Inter-droplet distance, particle size and encapsulation efficiency was affected by the ratio of dispersed to continuous phases flow rates. Drug release from microbeads was also affected by the nature of monomers. Difunctional mo-nomers tend to retard the release rate while addition of monofuntional mono-mer improves the release rate. Thus it was found that the developed micro-fluidic device can tune quite precisely the release properties of drug loaded polymer microparticles. In future, this setup could be used to encapsulate other hydrophilic or hydrophobic drug for desired applications.

REFERENCES1. Delie, F., Blanco-Príeto, M., 2005.

Polymeric Particulates to Improve Oral Bioavailability of Peptide Drugs. Molecules 10, 65-80.

2. Holgado, M.A., Arias, J.L., Cózar, M.J., Alvarez-Fuentes, J., Gañán-Calvo, A.M., Fernández-Arévalo, M., 2008. Synthesis of lidocaine-loaded PLGA microparticles by flow focu-sing: Effects on drug loading and re-lease properties. International Jour-nal of Pharmaceutics 358, 27-35.

3. Khan, I.U., Serra, C.A., Anton, N., Vandamme, T., 2013. Continuous-flow encapsulation of ketoprofen in copolymer microbeads via co-axial microfluidic device: Influence of operating and material parameters on drug carrier properties. Inter-national Journal of Pharmaceutics 441, 809-817.

4. Serra, C.A., Chang, Z., 2008. Micro-fluidic-Assisted Synthesis of Poly-

.ARTICLE.

Fig3: FTIR spectra, stretching and bending vibrations of acrylate, stretching vibra-tions of ester (.....) and dimeric carboxylic and ketonic carbonyl group of ketopro-fen (--). (Adapted from Khan et al., 2013)

Fig 4: Cumulative ketoprofen release of various ethyl acrylate (EA) contents at pH 6.8 (A). Formulations prepared under various Qc/Qd showing different release profiles (B). (Adapted from Khan et al., 2013)

Ikram.Ullah.KhanCollege of Pharmacy, Government College University, Faisalabad, Pakistan

Ikram Ullah Khan obtained his Bachelor degree in Pharmacy from college of pharmacy Punjab Uni-versity Lahore Pakistan in 2005 and Masters in Pharmaceutics from the Faculty of Pharmacy Bahauddin Zakariya (BZ) University Multan, Pakistan in 2008. In the same year he joined the College of Pharmacy Government College University Faisalabad Pakistan as a lecture of Pharmaceutics. He is interested in formulation and development of micro and nanocarriers for drug delivery applications. Currently he is doing PhD from University of Strasbourg France (CAMB and ICPEES) focusing on microfluidic technique to obtain multiple mor-phologies for pharmaceutical ap-plications. He holds a scholarship from Government College Univer-sity Faisalabad Pakistan.

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Artificial Cells, Nanomedi-cine and Biotechnology

Vol. 41, Nb 2 (April 2013) http://informahealthcare.com/toc/anb/41/2

•. Preparation.of.magnetic.gelatin.nanoparticles.and.investigating.the.possible.use.as.chemotherapeutic.agentH. Yılmaz, Senay Hamarat SanlıerArtificial Cells, Nanomedicine, and Biotechnology Apr 2013, Vol. 41, No. 2: 69–77.

•. Characterization.and.cellular.interaction.of.fluorescent-labeled.PHEMA.nanoparticlesIlgım Göktürk, Veyis Karakoç, Meh-met Ali Onur, Adil DenizliArtificial Cells, Nanomedicine, and Biotechnology Apr 2013, Vol. 41, No. 2: 78–84.

•. Enhanced.solubility.and.oral.absorption.of.sirolimus.using.D-α-tocopheryl.polyethylene.glycol.succinate.micellesMin-Soo Kim, Jung-Soo Kim, Won Kyung Cho, Sung-Joo HwangArtificial Cells, Nanomedicine, and Biotechnology Apr 2013, Vol. 41, No. 2: 85–91.

•. Acne. vulgarism. treatment. using. ul-tra-short.laser.pulse.generated.by.mi-cro-.and.nano-ring.resonator.systemM. A. Jalil, J. Phelawan, M. S. Aziz, T. Saktioto, C. T. Ong, Preecha P. YupapinArtificial Cells, Nanomedicine, and Biotechnology Apr 2013, Vol. 41, No. 2: 92–97.

•. Effects.of.agitation.speed.on.the.ex.vivo.expansion.of.cord.blood.hema-topoietic.stem/progenitor.cells.in.stirred.suspension.cultureQiang Jing, Haibo Cai, Zheng Du, Zhaoyang Ye, Wen-song TanArtificial Cells, Nanomedicine, and Biotechnology Apr 2013, Vol. 41, No. 2: 98–102.

•. Adenovirus-mediated.bone.mor-phogenetic.protein-2.gene.trans-fection.of.bone.marrow.mesen-chymal.stem.cells.combined.with.nano-hydroxyapatite.to.construct.bone.graft.material.in.vitroW. C. Li, D. P. Wang, L. J. Li, W. M. Zhu, Y. J. ZengArtificial Cells, Nanomedicine, and Biotechnology Apr 2013, Vol. 41, No. 2: 103–108.

•. Design,.synthesis,.and.activity.of.2,3-diphosphoglycerate.analogs.as.allosteric.modulators.of.hemoglo-bin.O2.affinityTigist W. Kassa, Ning Zhang, Andre F. Palmer, Jason Shastri MatthewsArtificial Cells, Nanomedicine, and Biotechnology Apr 2013, Vol. 41, No. 2: 109–115.

•. Design.of.a.novel.gut.bacterial.adhe-sion.model.for.probiotic.applicationsL. Rodes, M. Coussa-Charley, D. Mari-nescu, A. Paul, M. Fakhoury, S. Abbasi, A. Khan, C.Tomaro-Duchesneau, S. PrakashArtificial Cells, Nanomedicine, and Biotechnology Apr 2013, Vol. 41, No. 2: 116–124.

•. Purification,.characterization,.and.investigation.of.in.vitro.inhibition.by.metals.of.paraoxonase.from.different.sheep.breedsKadir Erol, Nahit Gençer, Mikail Arslan, Oktay ArslanArtificial Cells, Nanomedicine, and Biotechnology Apr 2013, Vol. 41, No. 2: 125–130.

•. Novel.creatine.biosensors.based.on.all.solid-state.contact.ammonium-selective.membrane.electrodesM. Altikatoglu, E. Karakus, V. Erci, S. Pekyardımcı, I. IsildakArtificial Cells, Nanomedicine, and Biotechnology Apr 2013, Vol. 41, No. 2: 131–136.

•. High.productivity.bioethanol.fermentation.by.immobilized.Saccharomyces.bayanus.onto.car-boxymethylcellulose-g-.poly(N-vi-nyl-2-pyrrolidone).beadsM. Gökgöz, M. YiğitoğluArtificial Cells, Nanomedicine, and Biotechnology Apr 2013, Vol. 41, No. 2: 137–143.

Vol. 41, Nb 3 (April 2013) http://informahealthcare.com/toc/anb/41/3

•. Preparation.and.characterization.of.gelatin.hydrogel.support.for.immobilization.of.Candida.Rugosa.lipaseMehlika Pulat, Gulen Oytun AkalinArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 145–151.

•. Ultra-short.Laser.Pulse.Generated.by.a.Microring.Resonator.System.for.Cancer.Cell.TreatmentM. A. Jalil, C. T. Ong, T. Saktioto, S. Daud, M. S. Aziz, P. P. YupapinArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 152–158.

•. Improving.the.anti-diabetic.activity.of.GLP-1.by.fusion.with.globular.adiponectinM. Gao, Y. Tong, W. Li, X. Gao, W. YaoArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 159–164.

•. Amperometric.carbon.paste.enzyme.electrodes.with.Fe3O4.nanoparticles.and.1,4-Benzoqui-none.for.glucose.determinationPinar Esra Erden, Bülent Zeybek, Şule Pekyardimc, Esma KiliçArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 165–171.

•. Macroporous.PHEMA-based.cryo-gel.discs.for.bilirubin.removalIşik Perçin, Gözde Baydemir, Bahar Ergün, Adil DenizliArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 172–177.

•. Molecular.filter.on-chip.design.for.drug.targeting.useM. S. Aziz, B. Jukgoljan, S. Daud, T. S. Tan, J. Ali, P. P. YupapinArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 178–183.

•. Plant.asparaginase-based.aspara-gine.biosensor.for.leukemiaKuldeep Kumar, Mandeep Kataria, Neelam VermaArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 184–188.

•. Laboratory.diagnosis.of.swine.flu:.a.reviewNidhi Chauhan, Jagriti Narang, Shikha Pundir, Sandeep Singh, C. S. PundirArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 189–195.

•. Comparative.diffusivity.measure-ments.for.alginate-based.atomized.and.inkjet-bioprinted.artificial.cells.using.fluorescence.microscopyM. Mobed-Miremadi, B. Asi, J. Parasseril, E. Wong, M. Tat, Y. ShanArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 196–201.

•. Innovative.approaches.in.wound.healing:.trajectory.and.advancesManju Rawat Singh, Shailendra Saraf, Amber Vyas, Vishal Jain, Deependra SinghArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 202–212.

•. The.fabrication.of.nanosensor-based.surface.plasmon.resonance.for.IgG.detectionEmir Alper Türkoğlu, Handan Yavuz, Lokman Uzun, Sinan Akgöl, Adil DenizliArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 213–221.

•. QCM.biosensor.for.testing.the.inflammatory.response.to.blood-contacting.biomaterialsE. Haberal, N. Ugur, M. KocakulakArtificial Cells, Nanomedicine, and Biotechnology Jun 2013, Vol. 41, No. 3: 222–226.

BIBLIOGRAPHY

June 2013

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Journal of Microencapsulation

Vol. 30, Number 3 (2013)http://informahealthcare.com/toc/mnc/30/3

•. Improved.antifungal.activity.of.itraconazole-loaded.PEG/PLA.nanoparticlesS. Essa, F. Louhichi, M. Raymond, P. HildgenJournal of Microencapsulation May 2013, Vol. 30, No. 3: 205–217.

•. Relationship.between.the.solu-tion.thermodynamic.properties.of.naproxen.in.organic.solvents.and.its.release.profiles.from.PLGA.microspheresD. M. Aragón, J. E. Rosas, F. MartínezJournal of Microencapsulation May 2013, Vol. 30, No. 3: 218–224.

•. Improved.therapeutic.perfor-mance.of.dithranol.against.pso-riasis.employing.systematically.optimized.nanoemulsomesKaisar Raza, Om Prakash Katare, Arvind Setia, Amit Bhatia, Bhupin-der SinghJournal of Microencapsulation May 2013, Vol. 30, No. 3: 225–236.

•. Preparation,.characterization.and.anticancer.therapeutic.efficacy.of.cisplatin-loaded.niosomesHong Yang, Anping Deng, Jingqing Zhang, Jian Wang, Bin LuJournal of Microencapsulation May 2013, Vol. 30, No. 3: 237–244.

•. Effect.of.antioxidants.on.the.stabi-lity.of.ONO-1301,.a.novel.long-ac-ting.prostacyclin.agonist,.loaded.in.PLGA.microspheresTakahiro Uchida, Mai Hazekawa, Tomomi Morisaki, Miyako Yoshida, Yoshiki SakaiJournal of Microencapsulation May 2013, Vol. 30, No. 3: 245–256.

•. Design.and.formulation.of.mucoadhesive.microspheres.of.sitagliptinSree Harsha, Mahesh Attimard, Tanveer A Khan, Anroop B Nair, Bandar E Aldhubiab, Sibghatullah Sangi, Arshia ShariffJournal of Microencapsulation May 2013, Vol. 30, No. 3: 257–264.

BIBLIOGRAPHY

•. Effect.of.vesicle’s.membrane.pac-king.behaviour.on.skin.penetration.of.model.lipophilic.drugNurul Fadhilah Kamalul Aripin, Rau-zah Hashim, Thorsten Heidelberg, Dong-Keon Kweon, Hyun Jin ParkJournal of Microencapsulation May 2013, Vol. 30, No. 3: 265–273.

•. Microencapsulation.of.protein.into.biodegradable.matrix:.a.smart.solution.cross-linking.techniqueNaveen K. Bejugam, Sanjay G. Gayakwad, Akm N. Uddin, Martin J. D’souzaJournal of Microencapsulation May 2013, Vol. 30, No. 3: 274–282.

•. Preliminary.studies.on.the.deve-lopment.of.IgA-loaded.chitosan–dextran.sulphate.nanoparticles.as.a.potential.nasal.delivery.system.for.protein.antigensSameer Sharma, Heather A. E. Ben-son, Trilochan K. S. Mukkur, Paul Rigby, Yan ChenJournal of Microencapsulation May 2013, Vol. 30, No. 3: 283–294.

•. Natural.carriers.for.application.in.tuberculosis.treatmentHugo Costa, Ana GrenhaJournal of Microencapsulation May 2013, Vol. 30, No. 3: 295–306.

Vol. 30, Number 4 (2013)http://informahealthcare.com/toc/mnc/30/4

•. Physicochemical.characterization.and.in.vivo.evaluation.of.solid.self-nanoemulsifying.drug.delivery.system.for.oral.administration.of.docetaxelQizhe Quan, Dong-Wuk Kim, Nirmal Marasini, Dae Hwan Kim, Jin Ki Kim, Jong Oh Kim, Chul Soon Yong, Han-Gon ChoiJournal of Microencapsulation Jun 2013, Vol. 30, No. 4: 307–314.

•. Cell-based.delivery.of.glucagon-like.peptide-1.using.encapsulated.mesenchymal.stem.cellsC. Wallrapp, E. Thoenes, F. Thür-mer, A. Jork, M. Kassem, P. GeigleJournal of Microencapsulation Jun 2013, Vol. 30, No. 4: 315–324.

•. Characterization.of.the.spray.drying.behaviour.of.emulsions.containing.oil.droplets.with.a.structured.interfaceY. Serfert, J. Schröder, A. Mescher, J. Laackmann, M. Q. Shaikh, K. Rätzke, V. Gaukel, H. P. Schuch-mann, P. Walzel, H.-U. Moritz, S. Drusch, K. SchwarzJournal of Microencapsulation Jun 2013, Vol. 30, No. 4: 325–334.

•. Sustained-release.diclofenac.potassium-loaded.solid.lipid.microparticle.based.on.solidified.reverse.micellar.solution:.in.vitro.and.in.vivo.evaluationSalome Amarachi Chime, Anthony Amaechi Attama, Philip F. Builders, Godswill C. OnunkwoJournal of Microencapsulation Jun 2013, Vol. 30, No. 4: 335–345.

•. Utilization.of.catalytic.hydrolysis.of.ethyl.acetate.for.solvent.removal.during.microencapsulationMinjung Lee, Jookyung Kang, Hon-gkee SahJournal of Microencapsulation Jun 2013, Vol. 30, No. 4: 346–355.

•. Cytotoxicity.and.antitumour.activity.of.5-fluorouracil-loaded.polyhydroxybutyrate.and.cellulose.acetate.phthalate.blend.micros-pheresKiran Chaturvedi, Santosh Kumar Tripathi, Anandrao R. Kulkarni, Tejraj M. AminabhaviJournal of Microencapsulation Jun 2013, Vol. 30, No. 4: 356–368.

•. An.overview.of.preparation.and.evaluation.sustained-release.injectable.microspheresLiandong Hu, Hailei Zhang, Weihua SongJournal of Microencapsulation Jun 2013, Vol. 30, No. 4: 369–382.

•. Treatment.of.MPS.I.mice.with.microencapsulated.cells.overex-pressing.IDUA:.effect.of.the.pred-nisolone.administrationV. Lizzi Lagranha, Talita Giacomet de Carvalho, R. Giugliani, U. MatteJournal of Microencapsulation Jun 2013, Vol. 30, No. 4: 383–389.

•. Comparative.studies.of.poly(α-caprolactone).and.poly(D,L-lactide).as.core.materials.of.polymeric.micellesMan Theerasilp, Norased Na-songklaJournal of Microencapsulation Jun 2013, Vol. 30, No. 4: 390–397.

•. Synthesis.and.characterisation.of.alginate/chitosan.nanoparticles.as.tamoxifen.controlled.delivery.systemsA. Martínez, P. Arana, A. Fernández, R. Olmo, C. Teijón, M.D. BlancoJournal of Microencapsulation Jun 2013, Vol. d30, No. 4: 398–408

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June 2013

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